Up to a certain age of gestation, fetal skin heals with no or only very minor scar formation (also called scarless repair or scarless healing) after wounding (Dang C et al., Clin Plast Surg 2003: 30, 13-23), which indicates an optimal (balanced) orchestration (regulation) of a coordinated cellular response in fetal skin during a specific time period of gestation. Newborn, young and adult skin (corresponding to non fetal skin), however, heal with scar formation after wounding, which indicates that the coordinated cellular response in non-fetal skin is less optimal or less balanced than in fetal skin.
In large animals and humans, scarless repair after wounding occurs up to mid-gestation to the early third trimester. At around this time period, fetal wound healing transitions from scarless to healing with scar formation upon wounding of fetal skin. In skin, scarless repair in the fetus is characterized by regeneration of an organized dermis with normal appendages (hair follicle, sweat gland, apocrine gland). Scarless healing is believed to be, at least partially, the result of a relative lack of inflammation, what corresponds to a balanced (optimal) pro- and anti-inflammatory response after wounding.
The ability to heal scarlessly appears to be intrinsic to fetal skin and is probably the result of the orchestrated interaction of many regulatory proteins including cytokines. This is illustrated infra.
Scarless fetal wounds heal with little inflammation, and the onset of scarring during fetal repair correlates with the presence of an acute inflammatory infiltrate (G. P. Yang et al. Wound Rep Reg 2003; 11: 411-418). In addition, introduction of inflammation into normally scarless-healing wounds results in increases in collagen deposition and scarring. This suggests an important function of inflammation during scar formation. As the immune system develops and its resultant inflammatory response increases, scar formation occurs at the repair site. Synthesis and remodeling of the extracellular matrix (ECM) by wound fibroblasts is likely the major determinant of dermal architecture after repair. Differences between scarring and scarless collagen architecture may be partly explained by phenotypic differences between adult and fetal fibroblasts.
Fetal and adult fibroblasts display differences in synthetic rates of collagen, hyaluronic acid (HA), and other ECM components. In vitro, fetal fibroblasts synthesize more type III and IV collagen than their adult counterparts. Fetal fibroblasts can simultaneously proliferate (or grow) and synthesize collagen. Fetal fibroblasts have a greater ability to migrate into collagen gels than do adult fibroblasts. Increasing cell density diminishes HA production in the adult but has no effect on fetal fibroblast HA synthesis.
The transforming growth factor (TGF) isoforms TGF-beta 1 and TGF-beta 2 (both isoforms are growth factors; growth factors belong to the cytokine protein family) have profibrotic functions (induce fibrosis) and promote scar formation. Their expression is increased in normal wound healing, and exogenous administration of this growth factor to adult wounds increases collagen, proteoglycan, and inflammatory cell accumulation. TGF-beta 1 also decreases matrix metalloproteinases and increases endogenous inhibitors of matrix metalloproteinase expression, which may favor collagen accumulation and scarring. Moreover, treatment of adult rat wounds with neutralizing antibody to TGF-beta 1 and TGF-beta 2 reduces scar formation. Treatment with fibromodulin, a TGF-beta modulator, has also been reported to reduce postnatal scarring.
In addition, it appears that the relative proportion of TGF-beta isoforms and not the absolute amount of any one isoform determines the wound repair outcome. In scarless fetal wounds, TGF-beta 3 (isoform of TGF-beta) expression is increased while TGF-beta 1 expression is unchanged. Conversely, TGF-beta 1 expression is increased and TGF-beta 3 decreased in scarring fetal wounds. Treatment of adult rat wounds with exogenous TGF-beta 3 reduces scar formation. These data suggest that the ratio of TGF-beta 3 to TGF-beta 1 may determine whether skin architecture is restored or scar forms after wounding.
Interleukins (belong to the cytokine protein family) regulate the chemotaxis and activation of inflammatory cells. Interleukin-6 (IL-6) stimulates monocyte chemotaxis and macrophage activation while interleukin-8 (IL-8) attracts neutrophils and stimulates neovascularization. Wounding stimulates a rapid increase in IL-6 and IL-8, which persists in the adult but disappears quickly in the fetus. Platelet-derived growth factor (PDGF, growth factor belonging to the cytokine protein family) induces adult fibroblast production of IL-6. In turn, the addition of IL-6 to fetal wounds produces early scarring. In fetal, compared to adult, fibroblasts IL-6 and IL-8 expression are lower at baseline and after stimulation with PDGF. Interleukin-10 (IL-10) has an anti-inflammatory function by decreasing production of IL-6 and IL-8. For instance, it has been shown in adult mouse that wounds treated with an IL-10 overexpressing adenoviral vector exhibited reduced inflammation and scarless healing.
PDGF and the fibroblast growth factor (FGF) family are additional profibrotic cytokines. PDGF, a potent mitogen and chemoattractant for fibroblasts, has prolonged expression during scar formation but disappears quickly in fetal wounds. For instance, it was shown that treatment of fetal rabbit wounds with PDGF induces a marked increase in acute inflammation, fibroblast recruitment, and collagen deposition. The FGF family of cytokines, including keratinocyte growth factor-1 and -2 (growth factors belonging to the cytokine protein family), has greater expression with increasing gestational age in fetal skin and during adult wounding.
In contrast, a mitogen for endothelial cells, vascular endothelial growth factor (VEGF, growth factor belonging to the cytokine protein family), increases twofold in scarless wounds while its expression remains unchanged in scarring fetal wounds. Thus, an increased stimulus for angiogenesis and vascular permeability may assist the rapid healing of fetal wounds.
The precise mechanisms of scarless healing remain unknown, despite the great increase in knowledge gained over the past decade. Scarless fetal wound repair is a tightly regulated (orchestrated) process involving various cellular mediators such as cytokines and other proteins.
Current therapies do not provide a mechanism for scarless healing. Therefore, it is an object of the present invention to provide compositions and methods to use the disclosed compositions to treat subjects suffering from a skin condition, disorder or disease and in need of scarless healing and/or in need of a balanced response to skin inflammation.